Processes for preparation of organic compounds

ABSTRACT

The present invention provides a method for preparing an organic compound, which comprises a dehydration step of distilling off water from a polar organic solvent solution containing the organic compound and water to bring the concentration of water below a given level, wherein the dehydration step comprises distilling off water together with the polar organic solvent while adding a polar organic solvent to the solution, or comprises repeating several cycles of adding a polar organic solvent to the solution and then distilling off water together with the polar organic solvent. The present invention further provides the preparation of an organic compound, which enables efficient isolation of the target product in high isolated yield from a polar organic solvent solution containing the organic compound, water and, if necessary, a compound which produces, upon coming into contact with water or the like, a substance accelerating the decomposition of the organic compound.

TECHNICAL FIELD

The present invention relates to a dehydration method for a polarorganic solvent solution containing an unstable organic compound andwater.

BACKGROUND ART

A compound having a β-lactam ring in its molecule (hereinafter referredto as a “β-lactam compound”) is useful as an antibacterial agent withpotent antibacterial activity. A wide variety of β-lactam compounds havebeen developed as antibacterial agents and various β-lactam compoundshave been produced on an industrial scale.

Although such a β-lactam compound is characterized by having a β-lactamring in its molecule, this β-lactam ring may be decomposed depending onthe type of its substituent, the type of its condensed ring, and/orenvironmental conditions surrounding its solution (e.g., heat, thepresence of water, the property thereof (acidic or alkaline)). For thisreason, when β-lactam compounds are to be produced, as mild conditionsas possible are selected for their production in order to prevent thecompounds from becoming decomposed and causing side reactions during theproduction process.

For example, a β-lactam compound (4) useful as an antibacterial agentcan be prepared by the reaction shown below.

However, when carrying out the above reaction to prepare β-lactamcompounds on an industrial scale, there is a problem arising from asignificant reduction in isolated yield during the step of isolating thetarget β-lactam compound (4) from the resulting reaction solution.

DISCLOSURE OF THE INVENTION

The present invention has been made by taking into consideration theabove situation, and aims to provide a method for preparing an organiccompound (e.g., a β-lactam compound), which enables efficient isolationof the target product in high isolated yield.

The inventors of the present invention have made a detailed examinationof the step where the target β-lactam compound (4) is isolated from thereaction solution obtained by the above reaction. As a result, thereason for the reduction in the isolated yield of the β-lactam compound(4) would be because in a dehydration step where water is distilled offtogether with THF from a reaction mixture containing the β-lactamcompound (4), distillation reduces the liquid level and hence the highlyconcentrated solution remaining on the wall surface of the reactionvessel becomes decomposed due to being heated on the vessel wallsurface.

In such a dehydration step where water is distilled off together withTHF from a reaction solution containing the β-lactam compound (4), theinventors of the present invention have found that when THF and waterare distilled off while adding THF to maintain the reaction solution ata constant level, it is possible to avoid the reduction in isolatedyield resulting from the decomposition of the β-lactam compound (4).Likewise, in the case of solvent replacement from THF to ethanol (usedas a crystallization solvent), they have also found that when THF isdistilled off while adding ethanol to maintain the reaction solution ata constant level, it is possible to isolate the target product in highisolated yield. They have made further attempts to adapt such atechnique to other cases and have completed the present invention.

Thus, the present invention provides a method for preparing an organiccompound, which comprises a dehydration step of distilling off waterfrom a polar organic solvent solution containing the organic compoundand water to bring the concentration of water below a given level,wherein the dehydration step comprises distilling off water togetherwith the polar organic solvent while adding a polar organic solvent tothe above polar organic solvent solution, or comprises repeating severalcycles of adding a polar organic solvent to the above polar organicsolvent solution and then distilling off water together with the polarorganic solvent.

In the method of the present invention, the above dehydration step ispreferably followed by a crystallization step of distilling off thepolar organic solvent from the resulting solution while supplementingthe solution with a poor solvent for the organic compound so as tocrystallize the organic compound. In this case, an alcohol solvent ispreferred for use as a poor solvent.

In the method of the present invention, the organic compound ispreferably a β-lactam compound, and more preferably a β-lactam compoundof Formula (1):

-   -   wherein A represents a condensed heterocyclic group having a        β-lactam ring structure, and B represents an optionally        substituted C₁-C₂₀alkyl group, an optionally substituted        C₂-C₂₀alkenyl group, an optionally substituted C₂-C₂₀alkynyl        group, an optionally substituted aryl group or an optionally        substituted heterocyclic group.

In the method of the present invention, the polar organic solventsolution is preferably a reaction solution obtained by reacting acompound of Formula (2):

-   -   wherein A represents a condensed heterocyclic group having a        β-lactam ring structure, and M represents a hydrogen atom or a        metal atom, in a polar organic solvent, with a        4-halogenomethyldioxolenone compound of Formula (3):    -   wherein R¹ and R² each independently represent a hydrogen atom,        an optionally substituted C₁-C₆alkyl group or an optionally        substituted phenyl group, or R¹ and R² may together form an        optionally substituted C₃-C₈ring, and X represents a halogen        atom, or a solution obtained by working up the reaction        solution.

MODES FOR CARRYING OUT THE INVENTION

The method of the present invention will be further described in moredetail below.

1) Polar Organic Solvent Solution

The method of the present invention comprises a dehydration step where apolar organic solvent solution containing an organic compound and wateris distilled to remove water together with the polar organic solvent.

(a) Organic Compound

Although there is no particular limitation on the organic compoundtargeted by the method of the present invention, it may be an organiccompound which is partially decomposed when exposed to long-term attackby heating in a water-containing organic solvent, especially an organiccompound whose decomposition is accelerated depending on the property ofwater contained in the organic solvent, more specifically under acidicor alkaline conditions. Such an organic compound may be preferred foruse in the method of the present invention.

As used herein, the term “decomposition” is intended to mean changinginto a compound which is structurally different from the original one.This term encompasses elimination of substituent(s), conversion into adifferent skeleton, complete breakdown of the skeleton, etc. There is noparticular limitation on the degree of decomposition; partial andcomplete decomposition of the original compound are both intended. Inparticular, in a case where the method of the present invention isapplied to industrial processes, a very slight decrease in yield willaffect the purity and product yield of final products. Thus, the methodof the present invention is preferably used when 0.1% to several % ofthe organic compound is decomposed.

Examples of such an organic compound include β-lactam compounds having aβ-lactam ring in their molecule; compounds having a hydroxy groupprotected with a hydrolyzable protecting group such as atetrahydrofuryloxy group, a tetrahydropyranyloxy group, a t-butoxygroup, a 1-ethoxyethoxy group, an acetoxy group, a trimethylsilyloxygroup, a triphenylmethoxy group or a 2,2,2-trichloroethoxy group; acetalcompounds; hemiacetal compounds; compounds having a C═N bond in theirmolecule; and compounds having an enolic hydroxy group protected with anacyl group.

Among these compounds, the method of the present invention is preferablyused as part of the production process for β-lactam compounds.

β-Lactam compounds are known as active ingredients of β-lactamantibacterial agents. As long as they have a β-lactam ring in theirmolecule, β-lactam compounds are not limited in any way and includemonocyclic compounds and condensed ring compounds. There is also nolimitation on the type and number of substituents attached to theβ-lactam ring. Among them, preferred are compounds whose moleculecarries a condensed heterocyclic group having a β-lactam ring, andparticularly preferred are compounds of the above Formula (1).

In the above Formula (1), A represents a condensed heterocyclic grouphaving a β-lactam ring. The following may be mentioned as examples ofsuch a condensed heterocyclic group having a β-lactam ring structure:

In the above formula, r¹ and r⁴ each represent a C₁-C₆alkyl group whichmay be substituted with G¹ or a benzoylamino group which may besubstituted with G¹.

r², r³, r⁵, r⁶, r⁷ and r⁸ each independently represent a hydrogen atom,a C₁-C₆alkyl group which may be substituted with G¹, a C₂-C₆alkenylgroup which may be substituted with G¹, a C₂-C₆alkynyl group which maybe substituted with G¹, an aromatic hydrocarbon group which may besubstituted with G¹ or a heterocyclic group which may be substitutedwith G¹.

In relation to the groups defined for r¹ to r⁸, examples of a C₁-C₆alkylgroup in the C₁-C₆alkyl group which may be substituted with G¹ include amethyl group, an ethyl group, a n-propyl group, an isopropyl group, an-butyl group, a sec-butyl group, a t-butyl group, a n-pentyl group anda n-hexyl group.

Examples of a C₂-C₆alkenyl group in the C₂-C₆alkenyl group which may besubstituted with G¹ include a vinyl group, a n-propenyl group, anisopropenyl group, a butenyl group, a pentenyl group and a hexenylgroup.

Examples of a C₂-C₆alkynyl group in the C₂-C₆alkynyl group which may besubstituted with G¹ include an ethynyl group, a n-propynyl group, anisopropynyl group, a butynyl group, a pentynyl group and a hexynylgroup.

Examples of an aromatic hydrocarbon group in the aromatic hydrocarbongroup which may be substituted with G¹ include a phenyl group, a1-naphthyl group and a 2-naphthyl group.

Likewise, examples of a heterocyclic group in the heterocyclic groupwhich may be substituted with G¹ include a 5- or 6-membered saturated orunsaturated heterocyclic group or a condensed heterocyclic group, eachof which contains 1 to 4 heteroatoms selected from an oxygen atom, anitrogen atom and a sulfur atom as ring member(s).

Specific examples include (i) 5-membered saturated heterocyclic groups,(ii) 5-membered unsaturated heterocyclic groups, (iii) 6-memberedsaturated heterocyclic groups, (iv) 6-membered unsaturated heterocyclicgroups and (v) condensed heterocyclic groups, as shown below.(i) 5-Membered Saturated Heterocyclic Groups

(ii) 5-Membered Unsaturated Heterocyclic Groups

(iii) 6-Membered Saturated Heterocyclic Groups

(iv) 6-Membered Unsaturated Heterocyclic Groups

(v) Condensed Heterocyclic Groups

Quinolinyl groups such as quinolin-2-yl, quinolin-3-yl, quinolin-4-yl,quinolin-5-yl, quinolin-6-yl, quinolin-7-yl and quinolin-8-yl, as wellas isoquinolinyl groups such as isoquinolin-1-yl, isoquinolin-3-yl,isoquinolin-4-yl, isoquinolin-5-yl, isoquinolin-6-yl, isoquinolin-7-yland isoquinolin-8-yl.

Examples of G¹ include a hydroxy group; a nitro group; a cyano group; ahalogen atom (e.g., a fluorine atom, a chlorine atom, a bromine atom); aC₁-C₆alkoxy group (e.g., a methoxy group, an ethoxy group, a n-propoxygroup, an isopropoxy group, a n-butoxy group, a t-butoxy group); atrialkylsilyloxy group (e.g., a trimethylsilyloxy group, atriethylsilyloxy group, a t-butyldimethylsilyloxy group); aC₁-C₆alkylthio group (e.g., a methylthio group, an ethylthio group, an-propylthio group, an isopropylthio group); a C₁-C₆alkylsulfinyl group(e.g., a methylsulfinyl group, an ethylsulfinyl group, an-propylsulfinyl group); a C₁-C₆alkylsulfonyl group (e.g., amethylsulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl group,an isopropylsulfonyl group, a n-butylsulfonyl group); an amino groupsubstituted with a C₁-C₆alkyl group (e.g., a methylamino group, anethylamino group, a n-propylamino group, an isopropylamino group); anamino group substituted with two C₁-C₆alkyl groups (e.g., adimethylamino group, a diethylamino group, a methylethylamino group); aC₁-C₆alkylcarbonyl group (e.g., an acetyl group, a propionyl group, apropylcarbonyl group); and a C₁-C₆alkoxycarbonyl group (e.g., amethoxycarbonyl group, an ethoxycarbonyl group, a n-propylcarbonylgroup, a t-butylcarbonyl group). The substituent G¹ may be attached atany position. Alternatively, the same or different substituents G₁ maybe attached at several positions.

In the above Formula (1), B represents an optionally substitutedC₁-C₂₀alkyl group, an optionally substituted C₂-C₂₀alkenyl group, anoptionally substituted C₂-C₂₀alkynyl group, an optionally substitutedaryl group or an optionally substituted heterocyclic group.

Specific examples of the above optionally substituted C₁-C₂₀alkyl groupinclude:

C₁-C₂₀alkyl groups, such as a methyl group, an ethyl group, a n-propylgroup, an isopropyl group, a n-butyl group, an isobutyl group, asec-butyl group, a t-butyl group, a n-pentyl group, a neopentyl group, an-hexyl group, an isohexyl group, a n-heptyl group, a n-octyl group, an-nonyl group and a n-decyl group;

-   -   C₁-C₂₀alkyl groups substituted with oxygen-containing        substituent(s), such as a methoxymethyl group, an ethoxymethyl        group, a 2-methoxyethyl group, a 3-methoxypropyl group and a        4-methoxybutyl group;    -   C₁-C₂₀alkyl groups substituted with sulfur-containing        substituent(s), such as a methylthiomethyl group, an        ethylthiomethyl group, a 2-methylthioethyl group, a        3-methylthiopropyl group and a 4-methylthiobutyl group;    -   C₁-C₂₀alkyl groups substituted with nitrogen-containing        substituent(s), such as a dimethylaminomethyl group, a        diethylaminomethyl group and a 2-dimethylaminoethyl group; and    -   C₁-C₂₀alkyl groups substituted with halogen atom(s), such as a        fluoromethyl group, a chloromethyl group, a bromomethyl group, a        difluoromethyl group, a dichloromethyl group, a difluoromethyl        group, a trifluoromethyl group, a trichloromethyl group, a        2,2,2-trifluoroethyl group, a pentafluoroethyl group, a        heptafluoropropyl group, a perfluorobutyl group and a        perfluoropentyl group.

Examples of a substituent in the optionally substituted C₂-C₂₀alkenylgroup or the optionally substituted C₂-C₂₀alkynyl group include anoxygen-containing substituent, a nitrogen-containing substituent, asulfur-containing substituent, and a halogen atom. On the other hand,examples of a C₂-C₂₀alkenyl or alkynyl group include the same groups aslisted above for G¹.

Examples of the above optionally substituted aryl group include a phenylgroup, a 4-methylphenyl group, a 2-chlorophenyl group, a 4-chlorophenylgroup, a 3-methoxyphenyl group, a 2,4-dimethylphenyl group, a 1-naphthylgroup, a 2-naphthyl group, a 4-chloro-1-naphthyl group and a6-methyl-2-naphthyl group.

The above optionally substituted heterocyclic group may be either amonocyclic heterocyclic group or a condensed heterocyclic group as longas it is a heterocyclic group containing 1 to 4 nitrogen atoms, oxygenatoms or sulfur atoms as ring member(s). Among them, preferred are a5-membered heterocyclic ring, a 6-membered heterocyclic ring and acondensed heterocyclic group, each of which contains 1 to 4 nitrogenatoms, oxygen atoms or sulfur atoms. Specific examples include the sameheterocyclic groups as listed above for r², r³, r⁵, r⁶, r⁷ and r⁸.

Examples of a substituent on the heterocyclic group defined for Binclude a nitro group; a cyano group; a halogen atom (e.g., a fluorineatom, a chlorine atom, a bromine atom, an iodine atom); a C₁-C₆alkoxygroup (e.g., a methoxy group, an ethoxy group, a n-propoxy group, anisopropoxy group, a n-butoxy group, a t-butoxy group); a C₁-C₆alkylthiogroup (e.g., a methylthio group, an ethylthio group, a n-propylthiogroup, an isopropylthio group, a n-butylthio group, a t-butylthiogroup); a C₁-C₆alkylsulfinyl group (e.g., a methylsulfinyl group, anethylsulfinyl group, a n-propylsulfinyl group, an isopropylsulfinylgroup, a n-butylsulfinyl group, a t-butylsulfinyl group); aC₁-C₆alkylsulfonyl group (e.g., a methylsulfonyl group, an ethylsulfonylgroup, a n-propylsulfonyl group, an isopropylsulfonyl group, an-butylsulfonyl group, a t-butylsulfonyl group); an amino groupsubstituted with one C₁-C₆alkyl group (e.g., a methylamino group, anethylamino group, a n-propylamino group); an amino group substitutedwith two C₁-C₆alkyl groups (e.g., a dimethylamino group, a diethylaminogroup, a dipropylamino group, an ethylmethylamino group, amethylpropylamino group); a C₁-C₆alkylcarbonyl group (e.g., an acetylgroup, a propionyl group); a C₁-C₆alkoxycarbonyl group (e.g., amethoxycarbonyl group, an ethoxycarbonyl group, a n-propoxycarbonylgroup, an isopropoxycarbonyl group, a n-butoxycarbonyl group, at-butoxycarbonyl group); an optionally substituted phenylsulfinyl group;an optionally substituted phenylsulfonyl group; and an optionallysubstituted phenylthio group. Two or more of these substituents, whichmay be the same or different, may be substituted at any position on theheterocyclic ring.

Examples of a substituent on the above phenylsulfinyl group,phenylsulfonyl group or phenylthio group include a halogen atom (e.g., afluorine atom, a chlorine atom, a bromine atom); a C₁-C₆alkyl group(e.g., a methyl group, an ethyl group); a C₁-C₆haloalkyl group (e.g., atrifluoromethyl group, a 2,2,2-trifluoroethyl group, a pentafluoroethylgroup); and a C₁-C₆haloalkoxy group (e.g., a trifluoromethoxy group, a2,2,2-trifluoroethoxy group, a pentafluoroethoxy group).

(b) Polar Organic Solvent

The polar organic solvent used in the present invention is not limitedin any way as long as it is an organic solvent composed of moleculeshaving a dipole moment. Examples include an ether solvent, a ketonesolvent, a halogenated hydrocarbon solvent, a nitrile solvent, an amidesolvent, a urea solvent, an ester solvent, a sulfur-containing solvent,and a halogenated aromatic hydrocarbon solvent.

Specific examples include ether solvents such as diethylether,tetrahydrofuran, 1,2-dimethoxyethane and 1,4-dioxane; ketone solventssuch as acetone, methylethylketone, methylisobutylketone andcyclohexanone; halogenated hydrocarbon solvents such as dichloromethane,chloroform, carbon tetrachloride and 1,2-dichloroethane; nitrilesolvents such as acetonitrile and benzonitrile; amide solvents such asN,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone andhexamethylphosphoramide; urea solvents such as1,3-dimethyl-2-imidazolidinone; ester solvents such as methyl acetate,ethyl acetate and n-propyl acetate; sulfur-containing solvents such asdimethyl sulfoxide and sulfolane; as well as halogenated aromatichydrocarbon solvents such as chlorobenzene, chlorotoluene,dichlorotoluene and chloroxylene. The polar organic solvent solution ofthe present invention may also comprise two or more of these polarorganic solvents.

Among them, preferred is a polar organic solvent that is available fordissolving both the organic compound and water and that can be readilydistilled off together with water. Examples of such a polar organicsolvent include an ether solvent and a ketone solvent. When using thesesolvents, it is preferable to apply the method of the present invention.Among them, an ether solvent is more preferred for use andtetrahydrofuran is particularly preferred for use.

(c) Water

Since there is no particular limitation on the amount (concentration) ofwater contained in the polar organic solvent solution used in thepresent invention, the method of the present invention can be appliedeven when using a polar organic solvent solution rich in water (e.g.,containing 50% by weight or more of water). Preferably, such awater-rich polar organic solvent solution may be treated using otheroperations (e.g., partition) to reduce its water content before beingprovided for the method of the present invention.

(d) Halogen Compound

The method of the present invention can preferably be used in a casewhere the above polar organic solvent solution contains an organiccompound, water and a compound which produces, upon coming into contactwith water or an alcohol solvent, a substance accelerating thedecomposition of the organic compound. A typical example of a substanceaccelerating the decomposition of the organic compound is a halogencompound.

Examples of such a halogen compound include a halogen (a simplesubstance; e.g., chlorine, bromine, iodine); a metal halogen compound(e.g., a metal chloride, a metal bromide, a metal iodide); and anorganic halogen compound (e.g., an organic chloride, an organic bromide,an organic iodide). Among these halogen compounds, the method of thepresent invention is particularly effective when the reaction systemcontains iodine or an alkali metal iodine compound. Examples of analkali metal iodine compound include lithium iodide, sodium iodide,potassium iodide, magnesium iodide, calcium iodide, ferric iodide, zinciodide, and cupric iodide.

Although the above polar organic solvent solution is not limited in anyway as long as it contains an organic compound and water, it ispreferably a reaction solution obtained by reacting a compound of theabove Formula (2) with a 4-halogenomethyldioxolenone compound of theabove Formula (3) in a polar organic solvent, or a solution obtained byworking up the reaction solution (e.g., by washing the reaction solutionwith water or the like and then collecting the organic layer). In thepresent invention, the latter solution is preferred because the presentinvention is preferably intended to ensure a higher yield in isolating atarget organic compound.

In the above Formula (2), A is as defined above.

M represents a hydrogen atom; an alkali metal such as lithium, sodium orpotassium; an alkaline earth metal such as magnesium or calcium; or atransition metal such as copper(I), copper(II), cobalt(II), cobalt(III),iron (II), iron (III), zinc(II) or manganese(II). In a case where Mrepresents an atom other than hydrogen, a compound of Formula (2) may bein either anhydride or hydrate form.

In the above Formula (3), R₁ and R₂ each independently represent ahydrogen atom, an optionally substituted C₁-C₆alkyl group or anoptionally substituted phenyl group.

Examples of a C₁-C₆alkyl group include a methyl group, an ethyl group, an-propyl group, an isopropyl group, a n-butyl group, a sec-butyl group,a t-butyl group, a n-pentyl group and a n-hexyl group.

Examples of a substituent on the above C₁-C₆alkyl group or phenyl groupinclude a nitro group; a cyano group; a halogen atom (e.g., a fluorineatom, a chlorine atom, a bromine atom, an iodine atom); a C₁-C₆alkoxygroup (e.g., a methoxy group, an ethoxy group, a n-propoxy group, anisopropoxy group, a n-butoxy group, a t-butoxy group); a C₁-C₆alkylthiogroup (e.g., a methylthio group, an ethylthio group, a n-propylthiogroup, an isopropylthio group, a n-butylthio group, a t-butylthiogroup); a C₁-C₆alkylsulfinyl group (e.g., a methylsulfinyl group, anethylsulfinyl group); a C₁-C₆alkylsulfonyl group (e.g., a methylsulfonylgroup, an ethylsulfonyl group, a n-propylsulfonyl group, anisopropylsulfonyl group, a n-butylsulfonyl group, a t-butylsulfonylgroup); an amino group substituted with one C₁-C₆alkyl group (e.g., amethylamino group, an ethylamino group, a n-propylamino group); an aminogroup substituted with two C₁-C₆alkyl groups (e.g., a dimethylaminogroup, a diethylamino group); a C₁-C₆alkylcarbonyl group (e.g., anacetyl group, a propionyl group); a C₁-C₆alkoxycarbonyl group (e.g., amethoxycarbonyl group, an ethoxycarbonyl group); as well as aphenylsulfinyl group which may be substituted with G², a phenylsulfonylgroup which may be substituted with G ², and a phenylthio group whichmay be substituted with G².

Examples of G² include a halogen atom (e.g., a fluorine atom, a chlorineatom, a bromine atom); a C₁-C₆alkyl group (e.g., a methyl group, anethyl group); a C₁-C₆haloalkyl group (e.g., a trifluoromethyl group);and a C₁-C₆haloalkoxy group (e.g., a trifluoromethoxy group).

Alternatively, R₁ and R₂ may together form an optionally substitutedC₃-C₈ring. Examples of a C₃-C₈ring include a cyclopentene ring, acyclohexene ring, a cycloheptene ring and a cyclooctene ring. Examplesof a substituent on the above ring include a C₁-C₆alkyl group (e.g., amethyl group, an ethyl group); a C₁-C₆alkoxy group (e.g., a methoxygroup, an ethoxy group, a n-propoxy group, an isopropoxy group, an-butoxy group, a t-butoxy group); a halogen atom (e.g., a fluorineatom, a chlorine atom); a C₁-C₆alkylthio group (e.g., a methylthiogroup, an ethylthio group); a substituted amino group (e.g., adimethylamino group, an acetylamino group); a nitro group; and a cyanogroup. One or more of these substituents, which may be the same ordifferent, may be substituted at any position.

Among them, preferred as R₁ and R₂ is a hydrogen atom or a C₁-C₆alkylgroup, and particularly preferred is a hydrogen atom or a methyl group.

The following may be mentioned as specific examples of a preferred4-halogenomethyldioxolenone compound of the above Formula (3):

A 4-halogenomethyldioxolenone compound of the above Formula (3) may beprepared and obtained, for example, by the method described in U.S. Pat.No. 4,448,732.

In the reaction between a compound of the above Formula (2) and a4-halogenomethyldioxolenone compound of the above Formula (3), aphase-transfer catalyst may be added for smooth progress of thereaction. Examples of such a phase-transfer catalyst include quarternaryammonium salts, such as tetraalkylammonium chlorides (e.g.,tetramethylammonium chloride, tetraethylammonium chloride,tetrapropylammonium chloride, tetrabutylammonium chloride (TBAC));tetraalkylammonium bromides (e.g., tetramethylammonium bromide,tetraethylammonium bromide, tetrapropylammonium bromide,tetrabutylammonium bromide); and benzyltrialkylammonium halides (e.g.,benzyltrimethylammonium chloride, benzyltrimethylammonium bromide,benzyl-tri-n-butylammonium chloride (BTBAC), benzyl-tri-n-butylammoniumbromide).

In the above reaction, when M in the above Formula (2) represents ahydrogen atom (i.e., the compound of Formula (2) is a carboxylic acid),it is preferable to add a base to the reaction system. Examples of abase available for use include an alkali metal hydroxide (e.g., sodiumhydroxide, potassium hydroxide); an alkaline earth metal hydroxide(e.g., magnesium hydroxide, calcium hydroxide); an alkali metalcarbonate salt (e.g., sodium carbonate, potassium carbonate); an alkalimetal bicarbonate salt (e.g., sodium bicarbonate, potassiumbicarbonate); an alkaline earth metal carbonate salt (e.g., magnesiumcarbonate, calcium carbonate); a metal hydride (e.g., sodium hydride,calcium hydride); a metal alkoxide (e.g., sodium methoxide, sodiumethoxide, potassium t-butoxide, magnesium methoxide, magnesiumethoxide); and an organic base (e.g., triethylamine, pyridine).

2) Dehydration Step

When the above polar organic solvent solution is distilled to removewater together with the polar organic solvent to obtain an organiccompound solution whose concentration of water is below a given level,the present invention is characterized by (a) distilling off watertogether with the polar organic solvent while continuously adding apolar organic solvent to the above solution, or by (b) repeating severalcycles of adding a given amount of a polar organic solvent to the abovesolution and then distilling off water together with the polar organicsolvent from the above solution. It has been found that by using theabove procedure (a) or (b), changes in the liquid level in a vessel canbe avoided and hence the adhesion of a highly concentrated solution ontothe vessel wall surface can be prevented. Consequently, the highlyconcentrated solution can be prevented from being heated and becomingdecomposed on the vessel wall surface.

The polar solvent to be added during the dehydration step may be thesame as or different from the polar solvent contained in the abovesolution. Specific examples include the same polar solvents as listedabove for those contained in the above solution.

In the present invention, it is possible to use either of the aboveprocedure (a) or (b). If the position of the liquid interface(horizontal surface) of the solution changes during the dehydrationstep, the residue of the solution will be heated more than necessary ina local area with a lowered interface position to increase the risk ofproducing a compound accelerating the decomposition of the organiccompound, thus facilitating the decomposition of the organic compound.For this reason, a heating area of the vessel is preferably kept atsubstantially the same position as that of the current liquid interfaceor at a lower position. In order to minimize changes in the liquidinterface caused by distillation of the solution, the amount of a polarorganic solvent to be added is preferably set to substantially the sameamount (volume) as that of the distilled-off polar organic solvent andwater.

The dehydration step may be accomplished in a vessel containing theabove solution. In a case where the above solution is a reactionsolution, the dehydration step may be performed continuously aftercompletion of the reaction in the reaction vessel used for the reaction.Alternatively, a reaction solution may also be transferred to anothervessel before being subjected to the dehydration step.

To distill off water together with the polar organic solvent from theabove solution, a vessel may be heated to a given temperature. Theheating temperature in a vessel will vary also depending on the type ofpolar organic solvent. A higher heating temperature in a vessel willimprove the work efficiency of the dehydration step, but too high aheating temperature can facilitate the decomposition of the organiccompound. Thus, the polar organic solvent and water are preferablydistilled off at as low temperature as possible by heating in a vacuumin order to ensure a higher efficiency in distilling off the polarorganic solvent and water while preventing the decomposition of theorganic compound.

Although the heating temperature for the solution and the degree ofvacuum in a vessel during the dehydration step can be determinedaccording to, e.g., the boiling point of the polar organic solvent to beused and the heat stability of the organic compound, it usually rangesfrom 0° C. to 80° C., preferably 10° C. to 70° C., and more preferably20° C. to 50° C. The internal pressure of the vessel during heatingranges from 1 to 100 kPa, and preferably 10 to 50 kPa.

Also, the dehydration step is preferably accomplished in a vesselequipped with known distillation equipment. The distillation equipmentis not limited in any way as long as it allows collection of thedistilled-off polar organic solvent and water. For example, distillationequipment having a piping system, a condenser tube and a collector maybe used for this purpose.

In the solution after the dehydration step, water should be removed tothe extent that the target organic compound can be obtained in highisolated yield. The water content in the solution after the dehydrationstep is usually 4% by weight or less, preferably 3.5% by weight or less,based on the total weight of the solution after the dehydration step.The water content in the solution after the dehydration step can bemeasured using a known water content meter (e.g., a Karl-Fishertitrator).

3) Crystallization Step

The organic compound is then isolated from the solution whose watercontent reaches below a given level.

Techniques used for isolation of the organic compound include, forexample, those involving: (i) distilling off the polar organic solventfrom the solution obtained in the dehydration step, and then adding acrystallization solvent to the residue to effect crystallization; (ii)distilling off the polar organic solvent from the solution obtained inthe dehydration step while supplementing the solution with acrystallization solvent to crystallize the organic compound; (iii)adding a recrystallization solvent to the residue to effectrecrystallization; or (iv) purifying the residue by the technique ofcolumn chromatography. As used herein, the term “crystallizationsolvent” is intended to mean an organic solvent having a low solubilityto the organic compound and preferably having a high solubility toimpurities, as specifically exemplified by solvents used forrecrystallization (recrystallization solvents) and solvents having aconsiderably low solubility to the organic compound to be crystallized(generally referred to as “poor solvents”). The distinction between poorsolvents and recrystallization solvents is not precise; which of them isused depends on the circumstances.

Among these techniques, (i) or (ii) is preferred for use and (ii) isparticularly preferred. Moreover, techniques (i) and (ii) allow greaterreduction in the amount of a crystallization solvent to be used whencompared to other techniques.

In the above technique (ii), to supplement the solution with acrystallization solvent, a given amount of the crystallization solventmay be added in divided portions or continuously at a constant rate,either of which may be used in the present invention. However, when thevolume of the solution is reduced during the crystallization step, thesolution is more likely to be concentrated locally at the liquidinterface. For this reason, in order to maintain the liquid interface ofthe solution at a constant position, the amount of a crystallizationsolvent to be added is preferably set to substantially the same amount(volume) as that of the distilled-off polar organic solvent.

Although the crystallization solvent to be used is not limited in anyway as long as it is a solvent having a low solubility to the organiccompound and allowing stable existence of the organic compound withoutcausing its decomposition, an alcohol solvent is preferred for use.

Examples of an alcohol solvent include C₁-C₆-alcohols such as methanol,ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, sec-butylalcohol, and t-butyl alcohol. Among them, C₁-C₃-alcohols are preferredfor use and ethanol is particularly preferred for use.

The crystallization step may be effected continuously in the same vesselwhere the above dehydration step has been performed. Alternatively, thesolution obtained in the dehydration step may also be transferred toanother vessel where the crystallization step will be performed.

The crystallization step may be accomplished by heating a vessel todistill off the polar organic solvent. The heating temperature in avessel will vary also depending on the type of polar organic solvent. Ahigher heating temperature will improve the work efficiency of thesolvent replacement step, but too high a heating temperature canfacilitate the decomposition of the organic compound. Thus, a vessel ispreferably heated in a vacuum in order to ensure a higher efficiency indistilling off the polar organic solvent at as low temperature aspossible.

The solution temperature in the crystallization step usually ranges from0° C. to 80° C., preferably 10° C. to 70° C., and more preferably 20° C.to 50° C. The internal pressure of the vessel during heating ranges from1 to 100 kPa, and preferably 5 to 50 kPa.

The concentration of the polar organic solvent in the solution after thecrystallization step is usually 5% by weight or less, preferably 3% byweight or less, and more preferably 1% by weight or less.

Once removal of the polar organic solvent has been completed, theresulting solution may be cooled to 10° C. or below, preferably 0° C. to10° C., to crystallize the target organic compound. The cooling timerequired for crystallization usually ranges from several tens of minutesto several hours.

The precipitated organic compound may be isolated, e.g., by filtrationor using a centrifugal separator to remove the crystallization solvent.The resulting organic compound may be subject to recrystallization orwashed with the same solvent as used for recrystallization orcrystallization, if desired.

According to the procedures described above, the target organic compoundcan be efficiently isolated. The structure of the resulting organiccompound may be confirmed by measuring its IR spectrum, mass spectrumand ¹H-NMR spectrum or by gas chromatography, high performance liquidchromatography, etc.

EXAMPLES

The present invention will now be further described in more detail inthe following examples, which are not intended to limit the scope of theinvention.

In the examples and comparative examples shown below, the startingmaterial(5R,6S)-6-(1-(R)-hydroxyethyl)-7-oxo-3-(2-(R)-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid sodium salt 2.5-hydrate was prepared according to the methoddescribed in JP 63-162694 A.

Example 1

(5R,6S)-6-(1-(R)-Hydroxyethyl)-7-oxo-3-(2-(R)-tetrahydrofuryl)-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylicacid sodium salt 2.5-hydrate (111.0 g, purity: 98.4%), potassium iodide(5.15 g), sodium bicarbonate (2.60 g) and BTBAC (3.87 g) were mixed inTHF (465 ml). To this mixture,4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene (50.48 g, purity: 97.2%) wasadded and stirred at 30° C. for 2 hours and then at 55° C. for 4 hours.After completion of the reaction, the reaction solution was washed oncewith water (155 ml) and twice with 20% aqueous sodium chloride (155 ml)which had been adjusted to pH 8 with potassium bicarbonate, followed byisolating the organic layer. In this way, a β-lactam compound solution(534.7 g, hereinafter referred to as “Solution A”) was obtained, whichcontained a β-lactam compound of Formula (5) (hereinafter referred to as“Compound (5)”), iodine compounds, water and THF. By quantitativeanalysis using high performance liquid column chromatography, Solution Awas found to contain the target Compound (5) in an amount of 22.44% byweight (yield: 97.4%). The water content in Solution A was about 4% byweight.

Solution A thus obtained was placed in a vacuum of 17.3 to 19.3 kPa andat a temperature of 20° C. to 32° C. (bath temperature: 40° C.) todistill off THF. Whenever about 90 ml of THF was distilled off, SolutionA was supplemented with 90 ml fresh THF. This procedure was repeatedthree times. In this way, a THF solution of Compound (5) was obtained.The resulting solution was a 0.9 L/mol solution of Compound (5). Whenthe water content in Solution A was measured, it was 0.47% by weight.

Solution A was then warmed to 75° C. and THF was distilled off to give aconcentrated THF solution of Compound (5) (about 0.25 L/mol in THF),followed by addition of ethanol (95 ml). The resulting solution wasstirred to give a homogenous solution and placed in a vacuum of 16 to 20kPa at 23° C. to 40° C. (bath temperature: 23° C. to 40° C.) to distilloff THF and ethanol. At this time, ethanol was added dropwise at aconstant speed to keep the solution volume unchanged, thus obtainingSolution B. The total amount of ethanol added dropwise was 105 ml.Solution B was a 1.2 L/mol solution of Compound (5).

Solution B was then cooled to 15° C. for 30 minutes to crystallizeCompound (5). The precipitated crystals were collected by filtration andwashed twice with cold ethanol (12 ml). The resulting crystals weredried to give crude crystals of Compound (5) (35.65 g) in 98.9% purityand 88.7% yield.

The crude crystals of Compound (5) were suspended in ethanol (180 ml)and heated at 60° C. for 10 minutes to completely dissolve the crystals.After this solution was filtered under pressure, the resulting filtratewas held at around 30° C. for 30 minutes and then placed in a vacuum of10.6 to 13.3 kPa at 30° C. to 35° C. to distill off 80 ml ethanol. Theresulting solution was then cooled at 15° C. for 30 minutes tocrystallize Compound (5). The crystallized crystals were collected byfiltration and washed twice with cold ethanol (13 ml) to give crystalsof Compound (5) in 99.5% purity and 85.1% yield.

Example 2

The same procedure as shown in Example 1 was repeated, except that thestep of distilling off THF from Solution A in a vacuum in Example 1 wasreplaced by the step of distilling off THF while adding dropwise THFthrough a nozzle reaching near the surface of Solution A. This exampleproduced substantially the same results as Example 1.

Comparative Example 1

In the step of distilling off THF from Solution A in Example 2, THF wasadded in one portion (not continuously) prior to distillation. The watercontent in the solution after distilling off THF was 2% by weight.Subsequently, the same procedure as shown in Example 1 was repeated toisolate Compound (5). Compound (5) was obtained in the same purity asExample 1, but its yield was reduced to as low as 80%.

Comparative Example 2

The same procedure as shown in Comparative Example 1 was repeated toisolate Compound (5), except that the step of distilling off THF inComparative Example 1 was followed by addition of ethanol in one portion(not continuously) to distill off ethanol and THF. Compound (5) wasobtained in the same purity as Example 1, but its yield was reduced toas low as 70%. In this case, the mother liquor was found to containCompound (5) in an amount corresponding to the reduction in yield. Whenthe mother liquor was analyzed for its solvent composition, THF wasfound to remain in a large amount, which would lead to the reduction inyield because Compound (5) could dissolve in THF. When the amount ofethanol added in one portion was increased 3-fold and the same procedurewas repeated, the same results as observed in Comparative Example 1 wereobtained for both purity and yield, but the amount of the solvent usedwas increased.

INDUSTRIAL APPLICABILITY

The present invention requires a shorter time for removal of water froma polar organic solvent solution, thus enabling prevention of prolongedheating and hence decomposition of an organic compound in a water-richpolar organic solvent, and also enabling efficient isolation of theorganic compound in high isolated yield. Moreover, when the polarorganic solvent is distilled off while adding a crystallization solvent,it is possible to reduce the total amount of the crystallization solventto be used. This is advantageous in terms of production costs.

1. A method for preparing an organic compound, which comprises adehydration step of distilling off water from a polar organic solventsolution containing the organic compound and water to bring theconcentration of water below a given level, wherein the dehydration stepcomprises distilling off water together with the polar organic solventwhile adding a polar organic solvent to the polar organic solventsolution, or comprises repeating several cycles of adding a polarorganic solvent to the polar organic solvent solution and thendistilling off water together with the polar organic solvent.
 2. Themethod for preparing an organic compound according to claim 1, whereinthe polar organic solvent solution contains a halogen compound whichproduces an acidic substance upon coming into contact with water or analcohol solvent.
 3. The method for preparing an organic compoundaccording to claim 2, wherein the halogen compound is an iodinecompound.
 4. The method for preparing an organic compound according toclaim 3, wherein the iodine compound is iodine or a metal iodide.
 5. Themethod for preparing an organic compound according to claim 1, whereinthe polar organic solvent solution is a solution in an ether solvent ora ketone solvent.
 6. The method for preparing an organic compound, whichcomprises the dehydration step according to claim 1, wherein thedehydration step is followed by a crystallization step of distilling offthe polar organic solvent from the resulting solution whilesupplementing the solution with a poor solvent for the organic compoundso as to crystallize the organic compound.
 7. The method for preparingan organic compound according to claim 6, wherein an alcohol solvent isused as the poor solvent.
 8. The method for preparing an organiccompound according to claim 1, wherein the organic compound is aβ-lactam compound.
 9. The method for preparing an organic compoundaccording to claim 1, wherein the organic compound is a β-lactamcompound of Formula (1):

wherein A represents a condensed heterocyclic group having a β-lactamring structure, and B represents an optionally substituted C₁-C₂₀alkylgroup, an optionally substituted C₂-C₂₀alkenyl group, an optionallysubstituted C₂-C₂₀alkynyl group, an optionally substituted aryl group oran optionally substituted heterocyclic group.
 10. The method forpreparing an organic compound according to claim 1, wherein the polarorganic solvent solution is a reaction solution obtained by reacting acompound of Formula (2):

wherein A represents a condensed heterocyclic group having a β-lactamring structure, and M represents a hydrogen atom or a metal atom, in apolar organic solvent, with a 4-halogenomethyldioxolenone compound ofFormula (3):

wherein R¹ and R² each independently represent a hydrogen atom, anoptionally substituted C₁-C₆alkyl group or an optionally substitutedphenyl group, or R¹ and R² may together form an optionally substitutedC₃-C₈ring, and X represents a halogen atom, or a solution obtained byworking up the reaction solution.